This proposal will enable the applicant to become an independent researcher in the field on neurogerontology. It will allow implemention of a comprehensive career development plan that will 1) expand the breadth of research skills into the area of oxidative biology and enhance current research skills, 2) fill knowledge gaps, and 3) accelerate publications and academic advancement. The research plan builds upon the applicants past (molecular biology) and present expertise and integrates the field of oxidative biology which is clearly justified for career development in neurogerontology. The aims are a balance of straightforward studies verifying and extending important preliminary findings of Apolipoprotein E (ApoE) isotype-specific dose responses, and relatively speculative, yet provocative and relevant examination of the role of oxidative stress in ApoE activity and expression. The research plan investigates the mechanistic relationship between ApoE and compensatory neural sprouting as one possible mechanism for the genetic risk for Alzheimer's disease (AD) associated with ApoE4 isotype and the protective effect for risk of the ApoE2 isotype. The overall hypothesis is that oxidative stress mechanisms associated specifically with the ApoE4 isotype inhibits its ability to support compensatory sprouting, and that this could lead to the earlier age of onset of AD in ApoE4 carriers. These studies primarily utilize an organotypic hippocampal slice culture paradigm to study these effects. The goal of the aims are to extend studies on the E3 and E4 isotypes to the protective isotype E2 which is still poorly understood compared to E3 and E4, and this represents a major knowledge gap in the understanding of the mechanism of ApoE risk and protection of AD. The studies extend previous results in postnatal mice into adult systems to demonstrate the possible relevance of these phenomena to AD mechanisms. The final goal is to test the oxidative hypothesis of ApoE4 and the possible regulation of ApoE expression by oxidative stress.